Type II or non-insulin dependent diabetes mellitus (NIDDM) is being recognized as an increasingly important cause of end-stage renal disease (ESRD). In Minnesota, diabetic nephropathy (DN) was responsible for half of all patients entering the ESRD program in 1988 and 1989. 76% of these patients had NIDDM while 24% had type I diabetes. The prevalence of NIDDM in various populations varies widely. In Wadena, Minnesota, the standardized prevalence of NIDDH in an adult population (20-60 years of age) was approximately 8%. In contrast, in the northern Minnesota American Indian reservations of Red Lake and Leech Lake, the prevalence was approximately 25%, i.e., three-fold greater. The prevalence of renal disease in American Indian NIDDM patients appears to be high as suggested by the Pima Indian studies. However, few data are available in other non-Pima American Indian populations to confirm these findings. Moreover, risk factors that may be important in the initiation as well as the progression of DN in NIDDM patients have not been studied. The Division of Nephrology and the Regional Kidney Disease Program at Hennepin County Medical Center, University of Minnesota Medical School, have developed an innovative reservation-based treatment program for American Indians with DN. This program has provided care to over 250 American Indians with ESRD, 80% of whom have NIDDH. Thus, our center is well poised to develop a broader based program to evaluate factors that may contribute to DN in NIDDM American Indians and to develop interventional strategies for this population. In addition, the long-standing interest of the University of Minnesota in diabetes, and in the natural history, pathology and pathogenesis of diabetic microvascular complications provides a unique combination of clinical and scientific expertise. Thus, in conjunction with the Indian Health Service, representatives of rural and urbanized American Indians and the University of Minnesota Medical School, we have developed a planning proposal 1) to define risk factors that may participate in the development of diabetic nephropathy, 2) to identify risk factors for the progression of established diabetic renal disease, and 3) to evaluate the availability and effectiveness of therapy for diabetic ESRD in the American Indian community.